DE602005004011T2 - HYDROISOINDOLIN tachykinin receptor antagonists - Google Patents

Description

BACKGROUND OF THE INVENTION

substance P is a natural one occurring undecapeptide, which belongs to the Tachykinin family of peptides belongs, the latter due to their immediate contractile action on extravascular Smooth muscle tissues are called so. The tachykinins are distinguished by a conserved carboxyl terminal sequence. In addition to substance P are the known mammalian tachykinins u. a. Neurokinin A and neurokinin B. The current nomenclature refers to the receptors for Substance P, neurokinin A and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2) or Neurokinin-3 (NK-3).

tachykinin and in particular substance P antagonists are useful in the treatment of clinical conditions, by the presence of a surplus at tachykinin activity and in particular substance P activity, including disorders of the Central nervous system, nociception and pain, gastrointestinal disorders, disorders bladder function and respiratory diseases.

NK-1 receptor antagonists are in the WO97 / 14671 disclosed.

SUMMARY OF THE INVENTION

The The present invention relates to certain hydroisoindoline compounds, which act as neurokinin-1 (NK-1) receptor antagonists and tachykinin and in particular substance P inhibitors are suitable. The invention relates also pharmaceutical formulations containing these compounds as Contain active ingredients, and the use of the compounds and their Formulations in the treatment of certain disorders, including vomiting, Urinary incontinence, depression and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

wobei:
R¹ ausgewählt ist aus der Gruppe, bestehend aus:

• (1) Wasserstoff,
• (2) C_1-6-Alkyl, welches unsubstituiert ist oder mit Halogen, Hydroxyl oder Phenyl substituiert ist,
• (3) Cyclopentenon, welches unsubstituiert oder mit Hydroxyl oder Methyl substituiert ist,
• (4) -(CO)-C_1-6-Alkyl,
• (5) -(CO)-NH₂,
• (6) -(CO)-NHC_1-6-Alkyl und
• (7) -(CO)-N(C_1-6-Alkyl)(C_1-6-alkyl),

X unabhängig ausgewählt ist aus der Gruppe, bestehend aus:

• (1) Wasserstoff,
• (2) Fluor und
• (3) Methyl,

und pharmazeutisch annehmbare Salze davon und einzelne Enantiomere und Diastereomere davon.The present invention relates to compounds of the formula I:

in which:
R ^{1 is} selected from the group consisting of:

• (1) hydrogen,
• (2) C _1-6 alkyl which is unsubstituted or substituted by halogen, hydroxyl or phenyl,
• (3) cyclopentenone which is unsubstituted or substituted by hydroxyl or methyl,
• (4) - (CO) -C _1-6 alkyl,
• (5) - (CO) -NH ₂ ,
• (6) - (CO) -NHC _1-6- alkyl and
• (7) - (CO) -N (C _1-6 -alkyl) (C _1-6 -alkyl),

X is independently selected from the group consisting of:

• (1) hydrogen,
• (2) fluorine and
• (3) methyl,

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

wobei R¹ und X hierin definiert sind,
und pharmazeutisch annehmbare Salze davon und einzelne Enantiomere und Diastereomere davon.An embodiment of the present invention comprises compounds of the formula Ia:

wherein R ¹ and X are defined herein,
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

wobei R¹ und X hierin definiert sind,
und pharmazeutisch annehmbare Salze davon und einzelne Enantiomere und Diastereomere davon.An embodiment of the present invention comprises compounds of the formula Ib:

wherein R ¹ and X are defined herein,
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

• (1) Wasserstoff,
• (2) C_1-3-Alkyl, das unsubstituiert oder mit Hydroxyl oder Phenyl substituiert ist,
• (3) Cyclopent-2-en-1-on, das unsubstituiert oder mit Hydroxyl oder Methyl substituiert ist,
• (4) -(CO)-C_1-3-Alkyl,
• (5) -(CO)-NH₂,
• (6) -(CO)-NHC_1-3-Alkyl und
• (7) -(CO)-N(C_1-3-Alkyl)(C_1-3-alkyl).

An embodiment of the present invention comprises compounds wherein R ^{1 is} selected from the group consisting of:

• (1) hydrogen,
• (2) C _1-3 alkyl which is unsubstituted or substituted by hydroxyl or phenyl,
• (3) cyclopent-2-en-1-one which is unsubstituted or substituted by hydroxyl or methyl,
• (4) - (CO) -C _1-3 alkyl,
• (5) - (CO) -NH ₂ ,
• (6) - (CO) -NHC _1-3 -alkyl and
• (7) - (CO) -N (C _1-3 alkyl) (C _1-3 alkyl).

• (1) Wasserstoff,
• (2) Methyl,
• (3) 2-Phenylethyl,
• (4) 2-Hydroxyethyl,
• (5) Cyclopent-2-en-1-on,
• (6) 5-Hydroxycyclopent-2-en-1-on,
• (7) 4-Hydroxycyclopent-2-en-1-on,
• (8) 2-Methylcyclopent-2-en-1-on,
• (9) Acetyl,
• (10) -(CO)-NH₂,
• (11) -(CO)-NHCH₃ und
• (12) -(CO)-N(CH₃)CH₃.

Within this embodiment, the present invention encompasses compounds in which R ^{1 is} selected from the group consisting of:

• (1) hydrogen,
• (2) methyl,
• (3) 2-phenylethyl,
• (4) 2-hydroxyethyl,
• (5) cyclopent-2-en-1-one,
• (6) 5-hydroxycyclopent-2-en-1-one,
• (7) 4-hydroxycyclopent-2-en-1-one,
• (8) 2-methylcyclopent-2-en-1-one,
• (9) acetyl,
• (10) - (CO) -NH ₂ ,
• (11) - (CO) -NHCH _3, and
• (12) - (CO) -N (CH ₃₎ CH _3.

Furthermore, within this embodiment, the present invention relates to compounds in which R ^{1 is} hydrogen.

Also within this embodiment, the present invention relates to compounds in which R ^{1 is} methyl, 2-phenylethyl or 2-hydroxyethyl.

welches unsubstituiert oder mit Hydroxyl oder Methyl substituiert ist.Also within this embodiment, the present invention relates to compounds in which R ¹ is:

which is unsubstituted or substituted by hydroxyl or methyl.

Also within this embodiment, the present invention relates to compounds wherein R ^{1 is} acetyl, - (CO) -NH ₂ , - (CO) -NHCH ₃ and - (CO) -N (CH ₃ ) CH ₃ .

A embodiment The present invention includes compounds in which X is hydrogen is. An embodiment The present invention includes compounds in which X is fluorine is. An embodiment The present invention includes compounds in which X is methyl is.

Specific embodiments of the present invention include a compound that is selected from the group consisting of the title compounds of the examples herein and pharmaceutically acceptable salts thereof and individual Enantiomers and diastereomers thereof.

The Compounds of the present invention may have one or more centers of asymmetry and thus as racemates and racemic mixtures, single Enantiomers, diastereomer mixtures and individual diastereomers occurrence. Other asymmetric centers may be present, depending on the Nature of the different substituents on the molecule. each such asymmetric center becomes independent two optical isomers generate, and it is envisaged that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are encompassed by the scope of this invention. The present invention is intended to include all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without preferred Stereochemistry. The independent ones Syntheses of these diastereomers or their chromatographic separations can as known in the art by suitable modification of the methodology disclosed herein. Your absolute stereochemistry can by X-ray crystallography crystalline products or crystalline intermediates which, if necessary, be derivatized with a reagent that is an asymmetric center known absolute configuration can be determined. If he wishes, can racemic mixtures of the compounds are separated, so that the individual enantiomers are isolated. The separation can be through well-known in the art, such as. B. by coupling a racemic mixture of compounds with a enantiomerically pure compound to give a diastereomeric mixture followed by separation of the individual diastereomers Standard methods, such. B. fractional crystallization or Chromatography. The coupling reaction is often the formation of Salts using an enantiomerically pure acid or Base. The diastereomeric derivatives can then be removed by cleavage of the added chiral residue converted to the pure enantiomers become. The racemic mixture of compounds can also be direct by chromatographic methods using chiral stationary phases be separated; these methods are well known in the art. Alternatively, any enantiomer of a compound may be stereoselective synthesis using optically pure starting materials or Reagents of known configuration are well-known in the art known methods are obtained.

to Naming of those discussed herein Compounds exist several acceptable methods.

To the For example, the above compound may be either "(3aR, 4R, 5S, 7aR) -tert-butyl-5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate" or "tert-butyl (3aR, 4R, 5S, 7aR) -5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate ". The core structure can generally be referred to as octahydroisoindole, hexahydroisoindoline, Perhydroisoindoline, Hydroisoindolin- or Hydroisoindolverbindung be designated.

As known to those skilled in the art, halo or halogen as used herein is intended to mean fluoro, chloro, bromo and iodo. Similarly, C _1-6 , as in C _1-6 alkyl, should be defined to indicate the group of 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement such that C _{1-6 8-} alkyl especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. A group designated as independently substituted with substituents may be substituted with several such substituents.

The Designation "pharmaceutical acceptable salts " Salts consisting of pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids, have been produced. Salts derived from inorganic bases are u. a. Aluminum, ammonium, calcium, copper, iron (II), iron (III) -, Lithium, magnesium, manganese (III), manganese (II), potassium, sodium, Zinc salts and the like. Particularly preferred are the ammonium, Calcium, magnesium, potassium and sodium salts. Salts in solid Can shape exist in more than one crystal structure and can too in the form of hydrates. Of pharmaceutically acceptable organic non-toxic bases derived salts are u. a. Salts of primary, secondary and tertiary Amines, substituted amines, including naturally occurring substituted ones Amines, cyclic amines and basic ion exchange resins, such as z. Arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, Ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, Methylglucamine, morpholine, piperazine, piperidine, polyamine resins, Procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, Tromethamine and the like. If the connection of the present Invention is basic, the Salts of pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, getting produced. Such acids are u. a. Acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, Ethane sulfone, fumaric, gluconic, glutaric, hydrobromic, hydrochloric, Isethion, Milk, Malay, Apples, Almond, Methane Sulfone, Slime, Saltpetre, Pamoa, Panthothene, Phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and like. Particularly preferred are citric, hydrobromic, Hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acid. you will understand that, as used herein, references to Compounds of the present invention also the pharmaceutical acceptable salts.

The Illustrative of the invention is the use of those in the examples and compounds disclosed herein. Special connections within The present invention is u. a. a connection that is selected from the group consisting of those disclosed in the following examples Compounds and pharmaceutically acceptable salts thereof and individual Diastereomers thereof.

The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions characterized by the presence of an excess of tachykinin activity, especially substance P activity. For example, an excess of tachykinin and especially substance P activity is implicated in a number of central nervous system disorders. Such disorders include disorders of mood such as depression or more specifically depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymia, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder, and cyclothymic disorder; Anxiety, such as Panic with or without agoraphobia, agoraphobia without panic history, specific phobias, for example, specific animal phobias, sociophobia, obsessive-compulsive disorder, stress diseases, including post-traumatic stress disorder and acute stress disorder, and generalized anxiety; Schizophrenia and other psychoses, for example schizophreniform disorders, schizoaffective disorders, delusional disorders, short lasting psychoses, common psychoses and psychosis with delusions or hallucinations; Delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as: Alzheimer's disease, senile dementia, Alzheimer's type dementia, vascular dementia and other dementias, for example due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or due of multiple ethiologies; Parkinson's disease and other extrapyramidal movement disorders such. B. drug-related movement disorders, for example, caused by neuroleptics Parkinsonism, neuroleptic malignant syndrome, caused by neuroleptics acute dystonia, caused by neuroleptics akathisias, caused by neuroleptics tardive dyskinesia and caused by drugs position tremor (postural tremor); sub punch-related disorders caused by the ingestion of alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidin derivatives, sedatives, hypnotics and anxiolytics, the substance-related disorders Dependency and abuse, intoxication, withdrawal, intoxication delirium, withdrawal delirium, persistent dementia, psychosis, mood disorders, anxiety, sexual dysfunction and sleep disorders; Epilepsy; Down syndrom; Demyelinating diseases, such. As MS and ALS, and other neuropathological disorders such. Peripheral neuropathy, for example, diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental and intercostal neuralgia, and other neuralgias; and cerebrovascular disorders due to acute or chronic cerebrovascular damage such. Cerebral infarction, subarachnoid haemorrhage and cerebral lavages.

tachykinin and in particular, substance P activity is also at nociception and pain involved. The compounds of the present invention will therefore be suitable in the prevention or treatment of Diseases and conditions, where pain predominates, including soft tissue and peripheral Damage, such as Acute trauma, osteoarthritis, rheumatoid arthritis, Musculoskeletal pain, especially after a trauma, backache, myofascial pain syndromes, headache, episiotomy pain and burns; deep and visceral pain, such as B. heart pain, Muscle pain, eye pain, orofacial pain, for example toothache, Abdominal pain, gynecological Pain, for example dysmenorrhea and labor pain; Pain associated with nerve and root damage, such as B. pain associated with peripheral nerve disorders, for example, nerve entrapment and plexus brachialis tears, amputation, peripheral neuropathies, Tic douloureux, atypical facial pain, Nerve root injury and arachnoiditis; Pain associated with carcinomas, often is referred to as cancer pain; Central nervous system pain, as z. B. Pain due to damage to the Backmarks or brain stem; Lower back pain; Sciatica; spondylitis ankylosan, gout; and scar pain.

tachykinin and in particular substance P antagonists may also be useful in the treatment of respiratory diseases, especially among those those with excessive mucus secretion are connected, such. B. chronic obstructive pulmonary disease, Bronchopneumonia, chronic bronchitis, cystic fibrosis and Asthma, adult respiratory distress syndrome and bronchospasm; inflammatory Diseases such. B. inflammatory Intestinal disease, psoriasis, fibrositis, osteoarthritis, rheumatoid Arthritis, pruritis and sunburn; Allergies, such as Eg eczema and rhinitis; Hypersensitivity disorders such as Against Poisonum (Rhus toxicodendron); Eye diseases such as Conjunctivitis, conjunctivitis vernalis and the like; ophthalmic conditions in connection with cell proliferation, such. Proliferative vitreoretinopathy; Skin diseases, such. B. contact dermatitis, atopic dermatitis, Urticaria and other eczematoid dermatitis. Tachykinin and In particular, substance P antagonists may also be useful in the treatment of neoplasia, including breast tumors, neuroganglioblastoma and small cell carcinomas, such as. Small cell lung cancer.

tachykinin and in particular substance P antagonists may also be useful in the treatment of gastrointestinal (GI) disorders, including inflammatory diseases and diseases of the GI tract, such. Eg gastritis, gastroduodenal ulcers, gastric carcinoma, gastric lymphoma, disorders, which are associated with the neural control of the intestines, Ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting, including acute, delayed or expected vomiting such. As vomiting, caused is caused by chemotherapy, radiation, toxins, viral or bacterial infections, Pregnancy, vestibular disorders, z. Motion sickness, dizziness, drowsiness and Meniere's disease, Surgery, migraine and variations in intercranial pressure, gastroesophageal reflux disease, Acid indigestion, excessive enjoyment of food or drinks, sour stomach, sour belching or regurgitation, heartburn, for example, episodic, nocturnal or heartburn and dyspepsia caused by food intake.

Tachykinin and especially substance P antagonists may also be useful in the treatment of a variety of other conditions, including stress-related somatic disorders; Reflex dystrophy of the sympathetic, such. Shoulder-hand syndrome; Immune defense reactions, such as. Rejection of transplanted tissues, and disorders due to immune enhancement or suppression, such as. Systemic lupus erythematosus; Plasma extravasation caused by cytokine chemotherapy, disorders of bladder function such as: Cystitis, hyperreflexia of the bladder detrusor, frequent urination and urinary incontinence, including the prevention or treatment of bladder overactivity with symptoms of urge incontinence, urinary urgency and urinary frequency; Fibrosis and collagen diseases such. B. Scleroderma and eosinophilic fascioliasis; Disorders of blood flow, caused by vasodilation, and vasospastic diseases, such. Angina, vascular headache, migraine and Reynaud's disease; and pain or nociception associated with or attributable to any of the aforementioned conditions, especially pain transmission in migraine.

The Compounds of the present invention are also suitable for treatment a combination of the above conditions, especially for treatment a combination of postoperative pain and postoperative Nausea and vomiting.

The Compounds of the present invention are particularly suitable for prevention or treatment of vomiting, including acute, delayed or expected vomiting, such as B. Vomiting that is caused through chemotherapy, radiation, toxins, pregnancy, vestibular disorders, Exercise, surgery, migraine and fluctuations in intercranial pressure. For example, the compounds are the optionally in combination with others antiemetic agents for the prevention of acute and delayed nausea and vomiting in conjunction with first-time and repeated moderate to strong emetogenic cancer chemotherapy, the high dose cisplatin includes, suitable. Especially, the compounds of the present invention Invention suitable for the treatment of vomiting caused is caused by antineoplastic (cytotoxic) agents, including the used routinely in cancer chemotherapy, and vomiting by other pharmacological agents, for example Rolipram, is caused. Examples of such chemotherapeutic Means are u. a. Alkylating agents, for example ethyleneimine compounds, Alkyl sulfonates and other compounds having an alkylating effect, such as Nitrosoureas, cisplatin and dacarbazine; Antimetabolites for example, folic acid, Purine or pyrimidine antagonists; mitotic inhibitors, for example Vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic Antibiotics. Specific examples of chemotherapeutic agents are, for example, by D.J. Stewart in Nausea and Vorniting: Recent Research and Clinical Advances, ed. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Fla., USA (1991), pages 177-203, in particular Page 188, described. Usually used chemotherapeutic agents are u. a. Cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide, Carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, Procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, Vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al. in Cancer Treatment Reports (1984) 68 (1), 163-172]. Also discloses the use of a compound of the present invention, a chronobiological (phase shift in the daily rhythm) To achieve an effect and to reduce circulatory disturbances in a mammal. Besides that is the use of a compound of the present invention for blocking the phase shift effects of light in a mammal.

Further discloses the use of a compound of the present invention Invention or a pharmaceutically acceptable salt thereof Increase or improve the quality of sleep and prevent it and treatment of sleep disorders and sleep disturbances in a mammal. Specifically, a method for increasing or improving the sleep quality by raising the sleep efficiency and improvement of sleep preservation revealed. About that In addition, a procedure for prevention and treatment of sleep disorders and sleep disturbances in a mammal discloses the administration of a compound of the present invention Invention or a pharmaceutically acceptable salt thereof. The treatment of sleep disorders, including falling asleep, is disclosed. and sleep disorders (Insomnia) ("DIMS"), due to psychophysiological causes, as a result of psychiatric disorders (in particular associated with anxiety), through medication and alcohol intake and Abuse (especially during Withdrawal stages) may occur childhood DIMS, nocturnal myoclonus, fibromyalgia, Muscle pain, sleep apnea and restless legs and nonspecific REM disorders, as they occur in old age.

The Particularly preferred disclosed embodiments are the treatment vomiting, urinary incontinence, depression or anxiety by administration the compounds of the present invention to a subject (human or animal) that needs such treatment.

The The present invention relates to a process for producing a Medicament for antagonizing the action of substance P on its Receptor site or to block neurokinin-1 receptors in a mammal, comprising the combination of a compound of the present invention with a pharmaceutical carrier or diluents. The present invention further relates to a process for the preparation a drug for the treatment of a physiological disorder in Connection with a surplus on tachykinins in a mammal, comprising the combination of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

Disclosed is a procedure for the treatment or prevention of physiological disorders, those with a surplus to Tachykininen, in particular substance P, are connected the method of administering a tachykinin reducing amount a compound of the present invention or a composition, containing a compound of the present invention, to a Patient who needs these includes. As used herein, the term "treatment" or "treating" means administration the compounds of the present invention to either the symptoms or the underlying cause of the indicated disease states a subject (human or animal) suffering from this condition or clinical indicators for it shows, reduce, alleviate or eliminate. The term "prevention" means the administration the compounds of the present invention to reduce the risk or the probability of occurrence of the specified disease states a subject (human or animal) that is susceptible or prone to this condition susceptible is to reduce, alleviate or eliminate it.

The Compounds of this invention are for antagonizing tachykinins, especially substance P, in the treatment of gastrointestinal disorders, Central nervous system disorders, Inflammatory diseases, Pain or migraine and asthma in a mammal, who needs such treatment suitable. This effect can be demonstrated by the following experiments become.

Receptor Expression in COS: To transiently express the cloned human neurokinin-1 receptor (NK1R) in COS, the cDNA for human NK1R was cloned into the expression vector pCDM9 derived from pCDM8 (INVITROGEN) by insertion of the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK +) into the Sac II site. Transfection of 20 μg of plasmid DNA into 10 million COS cells was performed by electroporation into 800 μl of transfection buffer (135 mM NaCl, 1.2 mM CaCl ₂ , 1.2 mM MgCl ₂ , 2.4 mM K ₂ HPO ₄ , 0.6 mM KH ₂ PO ₄ , 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 μF using the IBI GENEZAPPER (IBI, New Haven, CT). The cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin-streptomycin and 90% DMEM medium (GIBCO, Grand Island, NY) in 5% CO ₂ at 37 ° C for three days prior to the binding assay ,

Stable expression in CHO: In order to establish a stable cell line expressing the cloned human NK1R, the cDNA was subcloned into the pRcCMV vector (INVITROGEN). Transfection of 20 μg of plasmid DNA into CHO cells was achieved by electroporation into 800 μl of transfection buffer to which 0.625 mg / ml herring sperm DNA was added at 300 V and 950 μF using the IBI GENEZAPPER (IBI). Transfected cells were transfected into CHO medium [10% fetal calf serum, 100 U / ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa, KS), 0 , 7 mg / ml G418 (GIBCO)] in 5% CO ₂ at 37 ° C until colonies became visible. Each colony was separated and multiplied. The cell clone with the highest number of human NK1R was used for the following applications, such. For drug screening.

Experimental protocol using COS or CHO: The binding assay on human NK1R expressed in either COS or CHO cells is based on the use of ¹²⁵ I-substance P ( ¹²⁵ I-SP, from DU PONT, Boston, MA) as radioactive labeled ligand which competes with unlabeled substance P or with any other ligand for binding to human NK1R. Monolayer cell cultures of COS or CHO were dissociated through the nonenzymatic solution (SPECIALITY MEDIA, Lavallette, NJ) and reconstituted in an appropriate volume of the binding buffer (50mM Tris pH 7.5, 5mM MnCl ₂ , 150mM NaCl, 0.04mg / ml bacitracin, 0.004 mg / ml leupeptin, 0.2 mg / ml BSA, 0.01 mM phosphoramidon) so that 200 μl of the cell suspension contains about 10000 cpm of specific ¹²⁵ I-SP binding (about 50,000 to 200,000 cells). would cause. In the binding assay, 200 μl of cells were added to a tube containing 20 μl of 1.5 nM to 2.5 nM ¹²⁵ I-SP and 20 μl of unlabeled substance P or any other test compound. The tubes were incubated at 4 ° C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from the unbound radioactivity by a GF / C filter (BRANDEL, Gaithersburg, MD) previously moistened with 0.1% polyethylenimine. The filter was washed three times with 3 ml of washing buffer (50 mM Tris pH 7.5, 5 mM MnCl ₂ , 150 mM NaCl) and its radioactivity determined with a gamma counter. The activation of phospholipase C by NK1R may be measured by determining the accumulation of inositol monophosphate which is a degradation product of IP _3, as well as in CHO cells expressing the human NK1R. CHO cells are seeded in a 12-well plate with 250,000 cells per well. After 4 days of incubation in CHO medium, the cells are incubated overnight with 0.025 μCi / ml ³ H-myoinositol provided. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well to a final concentration of 0.1 mM with or without the test compound, and the incubation is continued at 37 ° C for 15 minutes. Substance P is added to the well at a final concentration of 0.3 nM, to activate human NK1R. After incubation at 37 ° C for 30 minutes, the medium is removed and 0.1N HCl added. Each well is sonicated at 4 ° C and extracted with CHCl ₃ / methanol (1: 1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantified with a beta counter. Specifically, by these experiments, the intrinsic tachykinin receptor antagonist effects of the compounds of the present invention can be demonstrated. The compounds of the following examples have an effect in the above experiment in the range of 0.05 nM to 10 μM. The action of the present compounds can also be demonstrated by the experiment disclosed by Lei et al., British J. Pharmacol., 105, 261-262 (1992).

According to one Another or alternative aspect is the present invention a compound of the present invention for use as a Composition available, which can be administered to a subject, which is a reduction the amount of tachykinin or substance P needed in his body.

The "Composition" as used herein is intended to include a product containing the specified ingredients in predetermined amounts or proportions, as well as any product containing directly or indirectly by combination of the specified ingredients results in the specified amounts. This term in relation pharmaceutical compositions should comprise a product, the one or more active ingredients and an optional carrier contains inert components, and any product that is directly or indirectly Complexation or aggregation of any two or more components or other types of reactions or interactions from one or more of the components. In general the pharmaceutical compositions are characterized by uniform and intimately bringing the active ingredient into contact with a liquid carrier or a finely divided solid support or both and, if necessary, subsequent shaping of the product to the desired Formulated. In the pharmaceutical composition is the desired one Active compound contained in an amount sufficient to over the course of or while the condition of the diseases achieves the desired effect. Accordingly, the pharmaceutical compositions of the present invention Any composition obtained by mixing a compound of the present invention and a pharmaceutically acceptable carrier is obtained. With "pharmaceutical acceptable "is meant that the wearer, the diluent or the excipient with the other ingredients of the formulation compatible is and for the recipient not harmful is.

to oral pharmaceutical compositions can be prepared according to a Any method known in the art for the preparation pharmaceutical compositions are prepared, and such Compositions can contain one or more agents selected from the group consisting from sweeteners, Flavorings, colorants and preservatives to pharmaceutical to give tasty and tasty preparations. tablets contain the active ingredient in a mixture with non-toxic pharmaceutical acceptable excipients suitable for the preparation of tablets are. These adjuvants can for example, inert diluents, such as Calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents, for example corn starch or alginic acid; Binder, for example starch, Gelatin or acacia gum; and lubricants, for example magnesium stearate, stearic acid or talc, his. The tablets can be coated be, or you can coated by known methods to delay the decomposition and absorption in the gastrointestinal tract and thereby an over a longer one Delayed period To give effect. Compositions for oral use may also as hard gelatin capsules in which the active ingredient with an inert solid diluent, For example, calcium carbonate, calcium phosphate or kaolin, mixed or as soft gelatin capsules in which the active ingredient with Water or an oil medium, for example, peanut oil, liquid paraffin or olive oil, is mixed, to be presented. Aqueous suspensions included the active ingredients in a mixture with excipients used for the production aqueous Suspensions are suitable. oil suspensions can formulated by suspending the active ingredient in a suitable oil become. Oil-in-water emulsions can also be used. Dispersible powders and granules, for producing an aqueous Suspension by adding water, make the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

The pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oily suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For the topical Ver For example, creams, ointments, gels, solutions or suspensions, etc. containing the compounds of the present invention can be used. The compounds of the present invention may also be formulated to be administered as an inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art.

The Compositions containing the compounds of the present invention can contain presented in unit dose form and by any of the be prepared in the field of pharmacy known methods. The term "unit dose form" is intended to be a single dose mean in which all effective and ineffective ingredients in a suitable system are combined so that the patient or the person administering the medicine to the patient single container or open a single package can, in which the total dose is included, and not any Components of two or more containers or packaging with each other must mix. Typical examples of unit dosage forms are Tablets or capsules for oral administration, single-dose ampoules for injection or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way but only typical examples of unit dosage forms in the field of pharmacy. The compositions, may also contain the compounds of the present invention presented as a kit in which two or more components, the active or inactive ingredients, carriers, diluents and the like could be, with instructions for making the actual dosage form by the Patient or a person giving the medicine to the patient administered, available be put. Such kits can with all necessary materials and components contained therein be equipped or you can Instructions for the use or manufacture of materials or Components that are independent have to be obtained by the patient or a person receiving the drug Patients administered.

By "pharmaceutically acceptable" is meant that the carrier, the diluent or the excipient with the other ingredients of the formulation compatible must be and for the recipient not harmful is.

The "Administration" or "administration" of a compound It should be understood that a compound of the invention the individual who needs treatment in a form provided which is in the body this individual in a therapeutically appropriate form and in a therapeutically effective amount can be incorporated, including, without but limited thereto to be: oral dosage forms such. For example, tablets, capsules, syrups, Suspensions and the like; Injectable dosage forms, such as. B. IV, IM or IP and the like; transdermal dosage forms, including creams, Gels, powders or patches; buccal dosage forms; Powders, sprays, Suspensions and the like for inhalation; and rectal suppositories. The term "therapeutic effective amount "means a sufficient amount of the compounds of the present invention in a suitable composition and in a suitable dosage form, to treat or prevent the specified disease states.

The compounds of the present invention may be administered in combination with another substance that has a complementary effect to the tachykinin and substance P inhibitors of the present invention. Accordingly, for the prevention or treatment of emesis, a compound of the present invention can be used in conjunction with other anti-emetic agents, particularly 5HT ₃ receptor antagonists, such as, e.g. As ondansetron, granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid such. B. dexamethasone, or GABA _B receptor agonists such. B. baclofen. Similarly, for the prevention or treatment of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as migraine. Ergotamines or 5HT ₁ agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as those disclosed in U.S. Pat. With norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), α-adrenoceptor antagonists, atypical antidepressants, benzodiazepines, 5 -HT _1A agonists or antagonists, especially 5-HT _1A partial agonists, corticotropin releasing factor (CRF) antagonists and pharmaceutically acceptable salts thereof. For treating or preventing eating disorders including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents. One will recognize that for the treatment or prevention of pain or nociception or inflammatory diseases, a compound of the present invention in association with an anti-inflammatory or analgesic agent, such as. B. an opiate agonist, a lipoxygenase inhibitor, such as. B. a 5-lipoxygenase inhibitor, a cyclooxygenase inhibitor, such as. B. a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as. An interleukin-1 inhibitor, an NMDA antagonist, a nitric oxide inhibitor, an inhibitor of nitric oxide synthesis, a non-steroidal anti-inflammatory drug, or a cytokine-suppressing anti-inflammatory agent.

you will recognize that, if any combination described herein is used, both the compound of the present invention as well as the other drug (s) to a patient within a reasonable period of time. The connections can in the same pharmaceutically acceptable carrier and thus simultaneously be administered. You can in separate pharmaceutical carriers, such as B. conventional oral dosage forms, which are taken at the same time become. The term "combination" also means the Case in which the compounds in separate dosage forms for disposal and administered sequentially. Therefore, for example an effective component can be administered as a tablet, and subsequently, within a reasonable time, the second effective Component either as an oral dosage form, such as. Legs Tablet, or as a fast dissolving oral dosage form be administered. With "fast-dissolving oral Formulation "is meant an oral delivery form that, when placed on the tongue of a Patients are given, dissolves in about 10 seconds. With "reasonable period" is a period meant not over about 1 hour. This means for example, that if the first effective component as a Tablet is provided, the second effective component then within one hour, either in the same type of dosage form or in another dosage form, which is an effective delivery the drug ensures should be administered.

The Compounds of this invention can in patients (animals and humans) who need such treatment in Doses administered to an optimal pharmaceutical Be effective. One will recognize that for use with a special one Application needed Dose may vary from patient to patient, not just with regard to on the chosen one special compound or composition, but also with regard to on the route of administration, the nature of the condition being treated, the age and condition of the patient, the accompanying medication or special diets, which the patient obeys, and other factors that the professionals the appropriate dose is ultimately at the discretion of the patient treating doctor.

at the treatment of conditions, which in conjunction with a surplus on tachykinins, is a suitable dose concentration of the compounds of the present invention Invention or the pharmaceutically acceptable salts thereof, about 0.001 to 50 mg / kg per day, in particular from about 0.01 to about 25 mg / kg, such as z. From about 0.05 to about 10 mg / kg per day. The dose range will generally be about 0.5 to 1000 mg per patient per day, which are administered in a single or multiple doses can. Preferably the dose range is about 0.5 mg to 500 mg per patient per day, more preferably about 0.5 mg to 200 mg per patient per day and most preferably about 5 mg to 50 mg per patient per day be. Special doses of the compounds of the present invention or pharmaceutically acceptable salts thereof for administration u. a. 1 mg, 5 mg, 10 mg, 30 mg, 100 mg and 500 mg. pharmaceutical Compositions of the present invention may be in a formulation containing about 0.5 mg to 1000 mg of active ingredient, preferably about 0.5 mg to 500 mg of active ingredient or 0.5 mg to 250 mg of active ingredient or 1 mg to 100 mg of active ingredient. Special pharmaceutical Compositions for treating or preventing a tachykinin excess contain about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg and 500 mg active substance.

Several methods for preparing the compounds of this invention are illustrated in the following examples. Starting materials and the required intermediates are commercially available in some instances or may be prepared according to literature procedures or as illustrated herein. All ¹ H NMR spectra were recorded on instruments with a field strength of 400 or 500 MHz.

EXAMPLE 1

(3aR,4R,5S,7aR)-5-{1(S)-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-1H-isoindol und (3aS,4S,5R,7aS)-5-{1(S)-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-1H-isoindol

(3aR, 4R, 5S, 7aR) -5- {1 (S) - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole and (3aS, 4S, 5R, 7aS) -5- {1 (S) - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

Step A: 2- (4-Fluorophenyl) -N-methoxy-N-methylacetamide

To a solution of 16.7 g (108.4 mmol) of (4-fluorophenyl) acetic acid in dry methylene chloride under a nitrogen atmosphere were added 13.8 g (141.5 mmol) of N, O-dimethylhydroxylamine, 20 ml of triethylamine, 14.2 g (119.3 mmol) of 4-dimethylaminopyridine (DMAP) and 27 g (140.6 mmol) of EDC. The reaction mixture was stirred for 2 hours at RT, then transferred to a separatory funnel. The mixture was washed sequentially with 2N aq. HCl, brine, saturated aq. NaHCO ₃ and brine. The organic layer was dried over desiccant, filtered, and the solvent was evaporated in vacuo to give 21 g of the crude title compound, which was used without further purification. ¹ H-NMR _(CDCl3): δ: 7.26 (2H, m), 7.02 (2H, m), 3.77 (2H, s), 3.65 (3H, s), 3.21 (3H, s).

Step B: 1- (4-fluorophenyl) but-3-en-2-one

To a solution of 220 mL (1.0 M, 220 mmol) vinylmagnesium bromide in 100 mL THF was added dropwise under a nitrogen atmosphere at 0 ° C a solution of 21 g (106.6 mmol) 2- (4-fluorophenyl) -N- methoxy-N-methylacetamide (step A) in ~ 150 ml of dry ether. The reaction mixture was stirred for 0.5 h at 0 ° C, then poured slowly into a mixture of ice / 2N HCl. The resulting mixture was diluted with ether and brine, transferred to a separatory funnel, and the organic layer separated. The organic layer was washed with brine, dried over desiccant, filtered, and the solvent was evaporated in vacuo to give 14.2 g of the crude title compound, which was used without further purification. ¹ H-NMR _(CDCl3): δ: 7.19 (2H, m), 7.02 (2H, t, J = 9.5 Hz), 6.42 (1H, dd, J ₁ = 14.2 Hz, J ₂ = 11 Hz), 6.34 (1H, d, J = 14.2 Hz), 5.86 (1H, d, J = 11 Hz), 3.87 (2H, s).

Step C: 1E- and 1Z-tert-butyl - {[1- (4-fluorobenzylidene) -prop-2-en-1-yl] oxy} dimethylsilane

To a solution of 104 mL (104.0 mmol, 1.2 equiv.) Of a 1.0 M solution of potassium t-butoxide in THF and 100 mL of dry THF under a nitrogen atmosphere at -78 ° C was added a solution of 14.2 g (86.6 mmol, 1 equiv) of 1- (4-fluorophenyl) but-3-en-2-one (Step B) and 13.0 g (86.6 mmol) of tert-butyl chlorodimethylsilane in 100 ml dry THF added. The mixture was stirred at -78 ° C for 6 hours and at RT for 6 hours, then quenched by the addition of 50 ml of water. The resulting mixture was warmed to RT, diluted with 150 mL of hexanes, transferred to a separatory funnel, and the organic layer separated. The organic layer was washed with 50 mL brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give 20.5 g of the crude title compound, which was used without further purification. ¹ H-NMR (CDCl ₃ ): δ: 7.52 (2H, m), 6.98 (2H, m), 6.33 (1H, dd, J ₁ = 13.2 Hz, J ₂ = 8, 5 Hz), 5.97 (1H, s), 5.52 (1H, d, J = 13.2 Hz), 5.17 (1H, d, J = 8.5 Hz).

Step D: (3aS, 4R, 7aR) -2-Benzyl-5 - {[tert -butyl (dimethyl) silyl] oxy} -4- (4-fluorophenyl) -3a, 4,7,7a-tetrahydro-1H -isoindole-1,3 (2H) -dione and (3aR, 4S, 7aS) -2-Benzyl-5 - {[tert -butyl (dimethyl) silyl] oxy} -4- (4-fluorophenyl) -3a, 4,7,7a-tetrahydro-1H-isoindole 1,3 (2H) -dione

A solution of 15 g (54.0 mmol, 1 equiv.) Of 1E- and 1Z-tert.-butyl - {[1- (4-fluorobenzylidene) -prop-2-en-1-yl] oxy} -dimethylsilane (step C) ) and 12.1 g (64.6 mmol) of N-benzylmaleimide in 150 ml of dry toluene under a nitrogen atmosphere was refluxed for 16 hours, then cooled to RT. The solvent was evaporated in vacuo to give 31 g of crude title compounds containing unreacted N-benzyl maleimide and used without further purification. ¹ H-NMR (CDCl ₃ ): δ: 7.37-7.26 (3H, m), 7.22 (2H, m), 7.00 (2H, m), 6.78 (2H, t, J = 8.5 Hz), 5.07 (1H, t, J = 2.3 Hz), 4.22 (1H, d, J = 16 Hz), 4.15 (1H, d, J = 16 Hz ), 3.66 (1H, d, J = 6.5 Hz), 3.52 (1H, t, J = 7.0 Hz), 3.14 (1H, m), 2.87 (1H, m), 2.68 (1H, m), 0.92 (1H, m), 0.78 (9H, s), 0.11 (3H, s), -0 , 1 (3H, s).

Step E: (3aS, 4S, 7aS) -2-Benzyl-5 - {[tert -butyl (dimethyl) silyl] oxy} -4- (4-fluorophenyl) -2,3,3a, 4,7,7a hexahydro-1H-isoindole and (3aR, 4R, 7aR) -2-Benzyl-5 - {[tert -butyl (dimethyl) silyl] oxy} -4- (4-fluorophenyl) -2,3,3a, 4,7,7a-hexahydro -1 H -isoindole

In a round bottom flask was 7.3 g (192.0 mmol, excess) of lithium aluminum hydride in dry ether under a nitrogen atmosphere at 0 ° C. To the resulting Mixture was added dropwise a solution of 31 g of the crude intermediate from Step D in 100 ml of dry methylene chloride under a nitrogen atmosphere. The resulting mixture was stirred at RT for 1 h, then carefully at 0 ° C by dropwise addition of 12 ml of water, then 10 ml of 5.0 N aq. NaOH, quenched. The resulting suspension was stirred at RT for 0.5 h touched and the solids are filtered off. The solvent of the filtrate was evaporated under vacuum to give the crude title compounds, which were used without further purification.

Step F: (3aS, 4S, 7aS) -2-Benzyl-4- (4-fluorophenyl) octahydro-5H-isoindol-5-one and (3aR, 4R, 7aR) -2-Benzyl-4- (4-fluorophenyl) octahydro-5H-isoindol-5-one

To a solution of the intermediate from Step E in 60 mL of dry acetonitrile under a nitrogen atmosphere at RT was added 100 mL (250 mmol) of a 2.5 M solution of HF in acetonitrile. The resulting mixture was stirred at RT for 16 h, then added dropwise with 120 mL of 5.0 N aq. NaOH quenched. The acetonitrile was evaporated in vacuo and the resulting aqueous mixture diluted with ether and water. The resulting mixture was transferred to a separatory funnel and the organic layer separated. The aqueous layer was extracted with a further portion of ether. The combined organic layers were washed with 50 mL brine, dried over desiccant, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc / hexanes (1/1) to give 9.0 g of the racemic title compounds. ¹ H-NMR _(CDCl3): δ: 7.27-7.23 (3H, m), 7.12-7.03 (2H, m), 3.75 (1H, d, J = 12.9 Hz, 3.61 (2H, d, J = 4.8 Hz), 3.61 (1H, q, J = 14.5 Hz), 2.93 (1H, t, J = 8.5 Hz), 2.68-2.52 (3H, m), 2.43-2.33 (2H, m), 2.25 (1H, m), 2.05 (2H, m).

Step G: (3aS, 4S, 5R, 7aS) -2-Benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol and (3aR, 4R, 5S, 7aR) -2-Benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol

To a solution of the intermediate (9.0 g) from Step F under a nitrogen atmosphere in dry ether at -78 ° C was added a 1.0 M solution of lithium aluminum hydride (38.3 ml) in ether. The resulting mixture was stirred for 0.5 h at -78 ° C, then cautiously by dropwise addition of water and then 5.0 N aq. NaOH quenched. The resulting suspension was stirred at RT for 0.5 h and the solids were filtered off. The solvent of the filtrate was evaporated under vacuum to give the crude title compounds as the main compounds which were used without further purification. ¹ H-NMR _(CDCl3): δ: 7.38-7.20 (7H, m), 7.05 (2H, t, J = 8.5 Hz), 3.75 (2H, s), 3 , 75 (1H, m), 2.8-2.65 (4H, m), 2.60 (1H, m), 2.50 (1H, m), 2.38 (1H, d, J = 8) , 1 Hz), 2.21 (1H, m), 1.95 (1H, m), 1.81 (2H, m), 1.73-1.62 (2H, m). MS: (MH) ⁺ 261.9.

Step H: (3aS, 4S, 5R, 7aS) -4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol and (3aR, 4R, 5S, 7aR) -4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol

The Intermediate from step G was at 50 psi hydrogen over 10 wt .-%. Hydrogenated 10% Pd-C in ethanol for 16 hours at RT. The catalyst was filtered off and the solvent The filtrate was evaporated under vacuum to give the crude title compounds to give, which were used without further purification.

Step I: tert-butyl (3aS, 4S, 5R, 7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-carboxylate and tert-butyl (3aR, 4R, 5S, 7aR) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-carboxylate

To a solution of 7.5 g (31.9 mmol) of the intermediate from Step H in dry methylene chloride under a nitrogen atmosphere at RT was added 9.0 g (41.5 mmol) of di-tert-butyl dicarbonate. The resulting mixture was stirred at RT for 16 h, then the solvent was evaporated in vacuo. The resulting mixture was dissolved in methanol and washed with 5.0 N aq. NaOH added. The resulting mixture was stirred for 2 hours and the methanol removed under vacuum. The watery Residue was diluted with EtOAc, transferred to a separatory funnel and the organic layer separated. The aqueous layer was extracted with a further portion of EtOAc. The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc / hexanes (1/4) as eluent to give 2.8 g of the racemic title compounds. ¹ H-NMR _(CDCl3): δ: ¹ H-NMR (CDCl _3): δ ¹ H-NMR _(CDCl3): δ 7.22 (2H, m), 7.07 (2H, m), 3 , 73 (1H, m), 3.48-3.33 (2H, m), 3.21-3.10 (2H, m), 2.51 (1H, m), 2.18 (1H, t , J = 10.7 Hz), 2.25 (1H, m), 1.98 (1H, m), 1.97-1.85 (1H, m), 1.63 (1H, m), 1 , 51-1.40 (1H, m), 1.49, 1.43 (9H, two singlets). Also isolated was a minor amount of the cis-alcohol (less polar) mixture: tert-butyl (3aR, 4R, 5R, 7aR) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-one. carboxylate and tert-butyl (3aS, 4S, 5S, 7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-carboxylate. ¹ H-NMR _(CDCl3): δ: 7.25 (2H, m), 7.05 (2H, m), 3.95 (1H, m), 3.50 to 3.20 (3H, m) , 3.08-2.95 (1H, two doublets, J = 14.3 Hz), 2.77 (1H, m), 2.65-2.55 (2H, m), 2.15 (1H, m), 1.82 (2H, m), 1.58 (1H, m), 1.45, 1.40 (9H, two singlets).

Step J: tert -butyl- (3aS, 4S, 5R, 7aS) -5 - {[3,5-bis (trifluoromethyl) benzoyl] oxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-one carboxylate and tert -butyl (3aR, 4R, 5S, 7aR) -5 - {[3,5-bis (trifluoromethyl) benzoyl] oxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-carboxylate

To a solution of 0.09 g (0.26 mmol) of the intermediate from Step 1 in dry methylene chloride under a nitrogen atmosphere at RT was added 0.089 g (0.32 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride, 0.07 ml TEA and a catalytic amount of DMAP added. The resulting mixture was stirred for 2 hours at RT, then transferred to a separatory funnel, washed with sat. aq. NaHCO ₃ , aq. KHSO ₄ and saline washed. The combined organic layers were dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to give 0.15 g of the crude title compounds, which were used without further purification. ¹ H-NMR _(CDCl3): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59-3.43 (2H, m), 3.30-3.20 (2H, m), 2.83 (1H, t, J = 12.7 Hz), 2, 62 (1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90-1.70 (2H, m), 1.55 , 1.47 (9H, two singlets).

Step K: tert -Butyl (3aS, 4S, 7aS) -5 - ({1- [3,5-bis (trifluoromethyl) phenyl] vinyl} oxy) -4- (4-fluorophenyl) octahydro-2H-isoindole -2-carboxylate and tert -butyl (3aR, 4R, 5S, 7aR) -5 - ({1- [3,5-bis (trifluoromethyl) phenyl] vinyl} oxy) -4- (4-fluorophenyl) octahydro-2H-isoindole -2-carboxylate

To a solution of 0.15 g (0.26 mmol) of the intermediate from Step J in dry THF under a nitrogen atmosphere at 0 ° C was added 2 mL of a 0.5 M solution of Tebbe reagent in toluene. The resulting mixture was stirred for 0.5 h at 0 ° C, then cautiously by dropwise addition of 0.5 mL of water, then 0.5 mL of 5.0 N aq. NaOH, quenched. The resulting suspension was diluted with ethyl acetate, stirred for 0.5 h at RT, and the solids were filtered off. The resulting filtrate was washed with 0.5 ml of 5.0 N aq. NaOH, and the solids were filtered through a pad of filter aid. The solvent was evaporated in vacuo to give the crude title compounds, which were used without further purification. ¹ H-NMR _(CDCl3): δ 7.73 (1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s), 4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81 (1H, t, J = 12.7 Hz), 2.60 (1H, m), 2.40-30 (2H, m), 1.98 (1H, m), 1, 83 (1H, m), 1.55, 1.47 (9H, two singlets).

Step L: tert -Butyl (3aS, 4S, 5R, 7aS) -5- {1R- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole- 2-carboxylate and tert-butyl (3aR, 4R, 5S, 7aR) -5- {1S- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-one carboxylate and tert-butyl (3aS, 4S, 5R, 7aS) -5- {1S- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2 carboxylate and tert-butyl (3aR, 4R, 5S, 7aR) -5- {1R- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-one carboxylate

The intermediate from step G was hydrogenated with 50 psi of hydrogen over 10% by weight of 10% Pd-C in ethanol for 16 hours at RT. The catalyst was filtered off and the solvent of the filtrate was evaporated under vacuum to give the crude title compounds, which were purified by prep. TLC with EtOAc / hexanes (1/3) to give the two diastereomers. The less polar (major) isomer, ¹ H-NMR _(CDCl3): δ: 7.73 (1H, s), 7.58 (2H, s), 7.25 (2H, m), 7.10 (2H, m), 4.05 (1H, m), 3.23-3.30 (3H, m), 3.20-3.07 (2H, m), 2.55 (1H, t, J = 10.3 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.20-1.55 (3H, m), 1.50, 1.43 (9H, two singlets ), 0.95 (3H, d, J = 6.9 Hz), 1.0-0.82 (1H, m). The minor isomer, ¹ H-NMR _(CDCl3): δ 7.70 (1H, s), 7.20 (2H, s), 6.95 (2H, m), 6.87 (2H, m), 4 , 45 (1H, m), 3.40 (1H, m), 3.27 (1H, m), 3.15-3.05 (2H, m), 2.47 (2H, t, J = 11 , 2 Hz), 2.15 (2H, m), 1.93 (1H, m), 1.75 (1H, m), 1.62 (1H, m), 1.50 (1H, m), 1.50, 1.45 (9H, s), 1.30 (3H, two doublets, J = 6.0 Hz).

Step M: (3aR, 4R, 5S, 7aR) -5- {1 (S) - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole and (3aS, 4S, 5R, 7aS) -5- {1 (R) - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

The less polar main diastereomer of the intermediate from Step L was dissolved in dry methylene chloride and stirred with anisole and TFA for 2 hours at RT. The solvent was evaporated in vacuo and the residue taken up in EtOAc. The solution was washed with aq. NaOH, then brine, washed, dried over desiccant and filtered. The solvent was evaporated under vacuum to give the crude title compounds. ¹ H-NMR _(CDCl3): δ 7.77 (1H, s), 7.60 (2H, s), 7.28 (2H, m), 7.12 (2H, t, J = 8.2 Hz), 4.07 (1H, m), 3.35 (1H, m), 3.22-3.10 (2H, m), 3.00 (1H, m), 2.85 (1H, d , J = 11.3 Hz), 2.65 (1H, t, J = 11.3 Hz), 2.50 (1H, m), 2.40 (1H, m), 1.87-1.68 (2H, m), 1.53 (1H, m), 1.30 (1H, m), 0.95 (3H, d, J = 6.0 Hz).

EXAMPLE 2

(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-1H-isoindol

(3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

Step A: (3aS, 4S, 5R, 7aS) -2-Benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol and (3aR, 4R, 5S, 7aR) -2-Benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol

outgoing of 3.5 g of the racemic mixture of (3aS, 4S, 5R, 7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol and (3aR, 4R, 5S, 7aR) -2-Benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol (Intermediate from example 1, step G), this mixture became by chiral HPLC using a CHIRACEL AD column with Hexanes / EtOH (9/1) as eluent, with the first eluting isomer (3aS, 4S, 5R, 7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol and the second eluting isomer (3aR, 4R, 5S, 7aR) -2-benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol were obtained.

Step B: tert-butyl (3aR, 4R, 5S, 7aR) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-carboxylate

To a solution of 5.36 g (15.8 mmol) of the second eluting isomer (3aR, 4R, 5S, 7aR) -2-benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol (inter from step A) in 80 mL of EtOH was added 4.31 g (19.7 mmol) of di-tert-butyl dicarbonate and 0.5 g of 10% Pd-C. The resulting mixture was hydrogen hydrogenated at RT for 50 h at 50 psi. The catalyst was filtered and washed with 5 ml of 5.0 N aq. NaOH added. The solvent was evaporated in vacuo. The aqueous residue was diluted with EtOAc, transferred to a separatory funnel, washed with brine, dried over desiccant, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc / hexanes (1/4) as eluent to give the title compound. ¹ H-NMR _(CDCl3): δ 7.22 (2H, m), 7.07 (2H, m), 3.73 (1H, m), 3.48-3.33 (2H, m), 3.21-3.10 (2H, m), 2.51 (1H, m), 2.18 (1H, t, J = 10.7Hz), 2.25 (1H, m), 1.98 (1H, m), 1.97-1.85 (1H, m), 1.63 (1H, m), 1.51-1.40 (1H, m), 1.49, 1.43 (9H , two singlets).

Step C: tert -Butyl (3aR, 4R, 5S, 7aR) -5 - {[3,5-bis (trifluoromethyl) benzoyl] oxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 carboxylate

To a solution of 4.75 g (14.0 mmol) of the intermediate from Step B in dry methylene chloride under a nitrogen atmosphere at RT was 4.71 g (17.0 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride, 2, Added 4 ml (17.3 mmol) TEA and a catalytic amount of DMAP. The resulting mixture was stirred at RT for 2 hours, then transferred to a separatory funnel, saturated with aq. NaHCO ₃ and brine. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give the crude title compound, which was used without further purification. ¹ H-NMR _(CDCl3): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59-3.33 (2H, m), 3.30-3.20 (2H, m), 2.83 (1H, t, J = 12.7 Hz), 2, 62 (1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90-1.70 (2H, m), 1.55, 1.47 (9H, two singlets).

Step D: tert -butyl- (3aR, 4R, 5S, 7aR) -5 - ({1- [3,5-bis (trifluoromethyl) phenyl] vinyl} oxy) -4- (4-fluorophenyl) octahydro-2H -isoindole-2-carboxylate

To a solution of 9.5 g (14.0 mmol) of the crude intermediate from Step C in dry THF under a nitrogen atmosphere at 0 ° C was added 66 mL (33 mmol) of a 0.5 M solution of Tebbe reagent in toluene , The resulting mixture was stirred for 2 hours at 0 ° C, then cautiously by dropwise addition of 7.5 mL of water, then 7.5 mL of 5.0 N aq. NaOH, quenched. The resulting suspension was stirred at RT for 0.5 h and the solids were filtered off. The resulting filtrate was washed with 5 ml of 5.0 N aq. Stirred NaOH for 16 hours and the solids filtered through filter aid. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc / hexanes (1/3) as eluent to give the title compound. ¹ H-NMR _(CDCl3): δ 7.73 (1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s), 4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81 (1H, t, J = 12.7 Hz), 2.60 (1H, m), 2.40-30 (2H, m), 1.98 (1H, m), 1, 83 (1H, m), 1.55, 1.47 (9H, two singlets).

Step E: tert -Butyl- (3aR, 4R, 5S, 7aR) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydroxy 2H-isoindole-2-carboxylate and tert-butyl (3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H- isoindole-2-carboxylate

A solution of 10.2 g of the crude intermediate from Step D in ethanol was hydrogenated at 50 psi of hydrogen over ~ 1 g of 10% Pd-C for 3 hours at RT. The catalyst was filtered off and the solvent of the filtrate was evaporated in vacuo to give the crude title compounds, which were purified by column chromatography with EtOAc / hexanes (2/3) as eluant to give 8.9 g (15.5 mol) of the two To give diastereomers with the main (S) -diastereomer. This mixture was taken up in ~ 150 mL of dry THF under a nitrogen atmosphere and treated with 80 mL (80 mmol) of a 1.0 M solution of potassium t-butoxide in THF. The resulting mixture was heated to 40 ° C for 1 hour, cooled to RT and quenched by the addition of water. The mixture was diluted with EtOAc, transferred to a separatory funnel, washed with brine, dried over desiccant, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with EtOAc / hexanes (1/3) to give the less polar tert-butyl (3aR, 4R, 5S, 7aR) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-carboxylate and the more polar tert-butyl (3aR, 4R, 5S, 7aR) -5- {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindole-2-carboxylate. ¹ H-NMR _(CDCl3): δ: of the less polar isomer: δ: 7.73 (1H, s), 7.58 (2H, s), 7.25 (2H, m), 7.10 (2H , m), 4.05 (1H, m), 3.23-3.30 (3H, m), 3.20-3.07 (2H, m), 2.55 (1H, t, J = 10 , 3 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.20-1.55 (3H, m), 1.50, 1.43 (9H, two singlets), 0.95 (3H, d, J = 6.9 Hz), 1.0-0.82 (1H, m). ¹ H-NMR (CDCl ₃ ) of the more polar isomer: 7.71 (1H, s), 7.20 (2H, s), 6.97 (2H, m), 6.85 (2H, m), 4, 47 (1H, m), 3,43-3,03 (4H, m), 2,47 (2H, m), 2,15 (2H, m), 1,92 (1H, t, J = 10, 5 Hz), 1.80-1.57 (3H, m), 1.50, 1.43 (9H, two singlets), 1.30 (3H, d, J = 6.9 Hz).

Step F: (3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole hydrochloride salt

The more polar diastereomer of the intermediate from Step E (1.5 g, 2.6 mmol) was dissolved in ~20 ml of 4 N HCl in dioxane and stirred at RT for 2 h. The solvent was evaporated in vacuo and the residue taken up in EtOAc. The solution was washed with aq. NaOH, then brine, washed, dried over desiccant and filtered. The solvent was evaporated in vacuo to give the crude title compound. Treatment with HCl in dioxane gave the HCl salt. ¹ H-NMR _(CDCl3): δ: 7.75 (1H, s), 7.37 (2H, s), 7.13 (2H, m), 6.87 (2H, t, J = 8, 5 Hz), 4.63 (1H, q, 6.5 Hz), 3.45 (1H, td, J ₁ = 4 Hz, J ₂ = 11.9 Hz), 3.17 (1H, m), 3.10 (1H, dd, J ₁ = 6.5 Hz, J ₂ = 9.5 Hz), 2.90 (1H, J = 12.7 Hz), 2.57 (2H, m), 2, 47 (1H, t, J = 9.5 Hz), 2.25 (1H, m), 1.98 (2H, m), 1.68 (1H, m), 1.10 (3H, d, 6 , 5 Hz). MS: (MH) ⁺ 475.9.

EXAMPLE 3

(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)-2-methyloctahydro-1H-isoindol

(3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) -2-methyloctahydro-1 H-isoindol

Step A: (3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) -2-methyloctahydro-1H- isoindole

To a solution of 30 mg (0.063 mmol) (3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole (Example 2) in ~ 2 mL of methanol was added ~20 mg (excess) of aq. Formaldehyde and 40 mg of sodium acetate was added. The resulting mixture was stirred at RT for 10 minutes, then 20 mg of NaBH _{4 was} added. The resulting mixture was stirred at RT for 1 h, then water was added. The methanol was evaporated in vacuo and the residue extracted with ether (2 x 25 ml). The combined extracts were dried over desiccant, filtered and the solvent was evaporated in vacuo. The residue was purified by prep. TLC with EtOAc / MeOH (9/1) as eluent to give the title compound. ¹ H-NMR (CDCl ₃ ): δ: ppm 7.68 (1H, s), 7.23 (2H, s), 7.02 (2H, m), 6.87 (2H, m), 4, 45 (1H, m), 3.27 (1H,), 2.78-2.65 (2H, m), 2.57 (2H, m), 2.45-2.30 (3H, m), 2.23-2.12 (2H, m), 1.98 (1H, m), 1.83-1.68 (2H, m), 1.30 (3H, 6.2) MS: (MH) ⁺ 489.9.

EXAMPLE 4

(3aS,4S,5R,7aS)-5-{(1S)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-1H-isoindol

(3aS, 4S, 5R, 7aS) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

Step A: tert -Butyl (3aS, 4S, 5R, 7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindole-2-carboxylate

The title compound was prepared from (3aS, 4S, 5R, 7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol (the first eluting isomer of Example 2, step A) according to the procedure for Example 2, step B, prepared. ¹ H-NMR _(CDCl3): δ: 7.22 (2H, m), 7.07 (2H, m), 3.73 (1H, m), 3.48-3.33 (2H, m) , 3.21-3.10 (2H, m), 2.51 (1H, m), 2.18 (1H, t, J = 10.7 Hz), 2.25 (1H, m), 1, 98 (1H, m), 1.97-1.85 (1H, m), 1.63 (1H, m), 1.51-1.40 (1H, m), 1.49, 1.43 ( 9H, two singlets).

Step B: tert -Butyl (3aS, 4S, 5R, 7aS) -5 - {[3,5-bis (trifluoromethyl) benzoyl] oxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 carboxylate

The title compound was prepared from the intermediate of Step A according to the procedure for Example 2, Step C. ¹ H-NMR _(CDCl3): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59-3.433 (2H, m), 3.30-3.20 (2H, m), 2.83 (1H, t, J = 12.7Hz), 2.62 ( 1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90-1.70 (2H, m), 1.55, 1 , 47 (9H, two singlets).

Step C: tert -Butyl (3aS, 4S, 5R, 7aS) -5 - ({1- [3,5-bis (trifluoromethyl) phenyl] vinyl} oxy) -4- (4-fluorophenyl) octahydro-2H -isoindole-2-carboxylate

The title compound was prepared from the intermediate of Step B according to the procedure for Example 2, step D, prepared. ¹ H-NMR _(CDCl3): δ 7.73 (1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s), 4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81 (1H, t, J = 12.7 Hz), 2.60 (1H, m), 2.40-2.30 (2H, m), 1.98 (1H, m), 1.83 (1H, m), 1.55, 1.47 (9H, two singlets).

Step D: tert -Butyl (3aS, 4S, 5R, 7aS) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydroxy 2H-isoindole-2-carboxylate and tert-butyl (3aS, 4S, 5R, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H- isoindole-2-carboxylate

The title compounds were prepared from the intermediate of Step C according to the procedure for Example 2, Step E. ¹ H-NMR _(CDCl3): δ: of the less polar isomer: δ: 7.73 (1H, s), 7.58 (2H, s), 7.25 (2H, m), 7.10 (2H , m), 4.05 (1H, m), 3.23-3.30 (3H, m), 3.20-3.07 (2H, m), 2.55 (1H, t, J = 10 , 3 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.20-1.55 (3H, m), 1.50, 1.43 (9H, two singlets), 0.95 (3H, d, J = 6.9 Hz), 1.0-0.82 (1H, m). ¹ H-NMR (CDCl ₃ ) of the more polar isomer: 7.71 (1H, s), 7.20 (2H, s), 6.97 (2H, m), 6.85 (2H, m), 4, 47 (1H, m), 3,43-3,03 (4H, m), 2,47 (2H, m), 2,15 (2H, m), 1,92 (1H, t, J = 10, 5 Hz), 1.80-1.57 (3H, m), 1.50, 1.43 (9H, two singlets), 1.30 (3H, d, J = 6.9 Hz).

Step E: (3aS, 4S, 5R, 7aS) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

The title compound was prepared from tert -butyl (3aS, 4S, 5R, 7aS) -5 - {(1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro -2H-isoindole-2-carboxylate (Step D) according to the procedure for Example 2, Step F. The more polar isomer, ¹ H-NMR _(CDCl3): δ: 7.68 (1H, s), 7.20 (2H, s), 7.05 (2H, m), 6.87 (2H, t, J = 8.2 Hz), 4.27 (1H, m), 3.28 (1H, m), 3.20-3.05 (2H, m), 2.88 (1H, m), 2, 72 (1H, d, J = 11.7 Hz), 2.58 (1H, t, J = 11.9 Hz), 2.40 (1H, m), 2.20 (1H, m), 2, 10 (1H, m), 1.92 (1H, m), 1.83 (1H, m), 1.60 (1H, m), 1.30 (3H, d, J = 6.0 Hz). MS: (MH) ⁺ 475.9.

EXAMPLE 5

3-[(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-on

3 - [(3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 -yl] cyclopent-2-en-1-one

To a solution of 12.3 mg (0.26 mmol) of (3aR, 4R, 5S, 7aR) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- ( 4-fluorophenyl) octahydro-1H-isoindole (Example 2) in ~2 mL of dry toluene was added 2.7 mg (0.028 mmol) of cyclopentane-1,3-dione and a catalytic amount (~0.5 mg) of PTSA. The resulting mixture was heated to reflux for 16 hours. The solvent was removed in vacuo and the residue was purified by prep. TLC with EtOAc / MeOh (95/5) as eluent to give the title compound. ¹ H-NMR _(CDCl3): δ: 7.73 (1H, s), 7.20 (2H, s), 7.03 to 6.90 (2H, m), 4.98, 4.80 ( 1H, s), 4.50 (1H, m), 3.62-3.18 (2H, m), 3.30-3.18 (3H, m), 3.15, 2.97 (1H, d, J = 11.2 Hz), 2.68 (2H, m), 2.55-2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J = 6.2 Hz). MS: (MH) ⁺ 556.0.

EXAMPLE 6

(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-1H-isoindol

(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

Step A: Diethyl 4 - {[tert -butyl (dimethyl) silyl] oxy} -3- (4-fluorophenyl) cyclohex-4-ene-1,2-dicarboxylate

A solution of 37 g (~80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl - {[1- (4-fluorobenzylidene) -prop-2-en-1-yl] oxy} dimethylsilane (Example 1, Step C) and 17 ml (18 g, 104.6 mmol) of diethyl (2E) -but-2-endioate in 200 ml of xylenes under a nitrogen atmosphere was heated at 160 ° C for 5 hours, then cooled to RT. The solvent was evaporated under vacuum to give an oil which without further Cleaning was used.

Step 13: Racemic diethyl (1S, 2S, 3R) -3- (4-fluorophenyl) -4-oxocyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S) -3- (4-fluorophenyl) -4-oxocyclohexane-1,2-dicarboxylate

To a solution of the above intermediate in 30 ml of acetonitrile under a nitrogen atmosphere at RT in a plastic reaction flask was added 200 ml (500 mmol) of a 2.5 M solution of HF in acetonitrile. The resulting mixture was stirred at RT for 24 hours. The reaction mixture was added to a mixture of 125 ml of 5.0 N aq. NaOH and 100 g of ice, then stirred for 5 minutes at RT. The resulting mixture was diluted with 300 ml of ether. The resulting mixture was transferred to a separatory funnel and the organic layer separated. The aqueous layer was saturated with NaCl, then extracted with a further portion of ether. The combined organic layer was washed with brine, dried over desiccant, filtered, and the solvent was evaporated in vacuo to give 40.8 g of the title compounds. ¹ H-NMR _(CDCl3): δ: 7.10 (2H, m), 7.05 (2H, m), 4.23 to 4.15 (2H, m), 3.90-3.80 ( 3H, m), 3.32 (1H, td, J ₁ = 13.0 Hz, J ₂ = 4.0 Hz), 3.21 (1H, t, J = 12.9 Hz), 2.68 ( 2H, m), 2.55 (1H, m), 2.07 (1H, m), 1.30 (3H, t, J = 7.2Hz), 0.85 (3H, t, J = 7 , 2 Hz).

Step C: Racemic diethyl (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S, 4R) -3- (4 fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate

To a solution of 40.2 g (119.3 mmol) of the intermediate from Step B in 150 mL of ethanol under a nitrogen atmosphere at -78 ° C was added 4.1 g (108.5 mmol) of NaBH ₄ powder. The resulting mixture was stirred at -78 ° C for 0.5 hours, then at RT for 2 hours. The reaction mixture was quenched cautiously by the addition of 30 ml of water and carefully quenched with 2N aq. HCl acidified. The solvent was evaporated in vacuo. The residue was dissolved in ether, transferred to a separatory funnel, washed with sat. aq. NaHCO ₃ and brine, dried over desiccant, filtered, and the solvent evaporated under vacuum to give the crude title compounds, which were purified in the next step. ¹ H-NMR _(CDCl3): δ: 7.25 (2H, m), 7.05 (2H, t, J = 8.2 Hz), 4.20-4.05 (2H, m), 3 , 85-3.72 (3H, m), 2.85 (2H, m), 2.70 (1H, t, J = 7.8 Hz), 2.25 (2H, m), 1.70 ( 1H, m), 1.60 (1H, m), 1.25 (3H, t, J = 7.2Hz), 0.85 (3H, t, J = 7.2Hz).

Step D: Diethyl (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate

outgoing of 21 g of the racemic mixture of diethyl (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S, 4R) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate (Step C) this was prepared by preparative Chiral HPLC using a CHIRACEL AD column with Heptanes / i-PrOH (9/1) as eluant to give 9.09 g of the desired first eluting isomer diethyl (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate to surrender.

Step E: (1S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl 2,2,2-trichloroethane imidoate

A solution of 25.82 g (100 mmol) of (1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol in 200 ml of dry Diethyl ether under a nitrogen atmosphere was cooled in an ice / water bath. Undiluted 3 ml (20 mmol, 0.2 equiv.) Of DBU were added to the reaction flask, then the mixture was stirred at 0 ° C for 10 minutes. Slowly, 15 ml (150 mmol, 1.5 equiv.) Of trichloroacetonitrile was added dropwise over 15 minutes. The reaction was stirred at 0 ° C for 2 hours, during which time it turned a deep yellow color. The volatiles were removed under vacuum in a cooling bath (<35 ° C) to give a light brown mobile liquid which was purified by column chromatography on silica gel (3 "x 10" cushion) in two batches with hexanes / EtOAc (9 / 1), then hexanes / EtOAc (4/1) was purified as eluent. The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a light yellow oil. ¹ H-NMR _(CDCl3): δ: 1.74 (3H, d, J = 6.5 Hz), 6.07 (1H, q, J = 6.5 Hz), 7.82 (1H, s ), 7.86 (2H, s), 8.40 (1H, br.s) ppm.

Step F: Diethyl (1S, 2S, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2 dicarboxylate

To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate (Step D ) and 21.5 g (53.5 mmol) of (1S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl 2,2,2-trichloroethane imidoate (Step E) in 250 ml of cyclohexane / 1.2 -Chloroethane (3/1) under a nitrogen atmosphere at -5 ° C was added 0.51 ml (3.58 mmol) of 54% HBF ₄ in ether. The reaction mixture was stirred at -5 ° C to 0 ° C for 2 hours, then diluted with ether. The mixture was washed with sat. aq. NaHCO ₃ washed. The organic layer was dried over desiccant, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc / hexanes (1/4) as eluent to give 9.2 g of the title compound as an oil. ¹ H-NMR _(CDCl3): δ: δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J = 8.5 Hz), 4.43 (1H, q, J = 6.0 Hz), 4.20-4.10 (2H, m), 3.80-3.73 (2H, m), 3, 36 (1H, m), 2.90-2.76 (2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63-1.55 (2H, m) , 1.33 (3H, d, J = 6.0 Hz), 1.25 (3H, t, J = 7.2 Hz), 0.82 (3H, t, J = 7.2 Hz). Unreacted starting alcohol could be recovered by purging the column with EtOAc and reused in the above reaction.

Step G: [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2- diyl] dimethanol

To a solution of 9.2 g (15.9 mmol) of diethyl (1S, 2S, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3 - (4-Fluoro-phenyl) -cyclohexane-1,2-dicarboxylate (Step F) in 100 ml of THF under a nitrogen atmosphere at RT was added 2 g (112.4 mmol, excess) of LiBH ₄ powder. The resulting mixture was heated to 68 ° C for 2 hours, then cooled to RT. The reaction mixture was quenched cautiously by addition of 30 mL of water, then extracted with EtOAc. The combined organic extracts were dried over desiccant, filtered and the solvent evaporated under vacuum to give 7.5 g of the crude title compound as an oil which was used without further purification. ¹ H-NMR (CDCl ₃ ): δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.87 (2H, t, J = 8, 2 Hz), 4.20 (1H, q, J = 6.0 Hz), 3.78 (1H, m), 3.67 (1H, m), 3.52 (1H, m), 3.30 -3.20 (2H, m), 2.58 (1H, t, J = 11.9Hz), 2.32 (1H, m), 1.87 (1H, m), 1.65 (1H, m), 1.58-1.35 (3H, m), 1.30 (3H, t, J = 6.0 Hz).

Step H: [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2- diyl] di (methylene) dimethanesulfonate

To a solution of 1.82 g (3.7 mmol) of [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3], cooled to -5 ° C. in an ice / salt bath. 5-Bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2-diyl] dimethanol (Step G) in 50 ml of methylene chloride was added 1.0 ml (3.5 equiv.) Of methanesulfonyl chloride, 2 , 1 ml (4 equiv.) Of TEA and 44 mg (0.1 equiv.) Of DMAP. The reaction mixture was stirred for 30 minutes at -5 ° C, then at this temperature by the addition of 20 ml of sat. aq. NaHCO ₃ quenched. The mixture was warmed to RT. The organic layer was separated and the aqueous layer extracted with another 50 ml of methylene chloride. The combined organic layer was washed with 20 mL 2N aq. HCl, 30 ml sat. aq. NaHCO ₃ , brine, dried over MgSO ₄ desiccant, filtered, and the solvent evaporated under vacuum to give the title compound as an oil, which was used without further purification.

Step I: (3aR, 4R, 5S, 7aS) -2-Benzyl-5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H -isoindole

In a pressure tube, a solution of crude [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2-diyl] di (methylene) dimethanesulfonate (step H) in ~ 20 ml of ethanol and 1.2 ml (~ 3 equiv.) of benzylamine. The pressure tube was sealed and heated in an oil bath at 150 ° C for 3 hours. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent removed under vacuum. The residue was diluted with 100 mL EtOAc, washed with 20 mL 5N aq. NaOH, dried over MgSO ₄ drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel with EtOAc as eluent to give 1.6 g of the title compound. ¹ H-NMR (CDCl ₃ ): δ: 7.35-7.20 (5H, m), 7.50 (2H, s), 6.97 (2H, m), 6.85 (2H, t, J = 8.2 Hz), 4.42 (1H, t, J = 6.0 Hz), 3.75 (2H, d, J = 13.4 Hz), 3.50 (2H, d, J = 13.4 Hz), 3.30 (1H, m), 2.96 (1H, m), 2.52 (3H, m), 2.19 (2H, m), 1.98 (1H, m) , 1.97 (1H, m), 1.86 (2H, m), 1.57 (1H, m), 1.33 (3H, t, J = 6.0 Hz), 1.30 (1H, m). MS: (MH) ⁺ 566.0.

Step J: (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H-isoindole

To a solution of (3aR, 4R, 5S, 7aS) -2-benzyl-5 - {(1R) - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1H- Isoindole (Step H) in ~50 mL EtOH was added 0.2 g (20 wt%) of 10% Pd (OH) ₂ -C. The reaction mixture was hydrogenated at 50 psi for 16 hours at RT. The catalyst was filtered off and the solvent of the filtrate was evaporated under vacuum to give the title compound. ¹ H-NMR _(CDCl3): δ: 7.70 (1H, s), 7.20 (2H, s), 6.95 (2H, m), 6.87 (2H, t, J = 8, 5 Hz), 4.42 (1H, q, J = 6.5 Hz), 3.55 (1H, m), 3.30 (1H, m), 3.10-2.95 (2H, m) , 2.83 (1H, m), 2.70 (1H, m), 2.52 (1H, m), 2.40 (1H, m), 2.10 (1H, m), 1.97 ( 2H, m), 1.80 (1H, m), 1.33 (3H, d, J = 6.2 Hz). MS: (MH) ⁺ 476.1.

EXAMPLE 7

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-on

3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 -yl] cyclopent-2-en-1-one

To a solution of 0.73 g (1.5 mmol) of (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- ( 4-fluorophenyl) octahydro-1H-isoindole (Example 6) in ~ 25 mL of dry toluene was added 0.166 g (1.7 mmol) of cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA. The resulting mixture was heated to reflux for 2 hours. The solvent was removed under vacuum and the residue was purified by prep. TLC with CHCl ₃ / 2N NH ₃ in MeOH (9/1) as eluent to give 0.49 g of the title compound. The compound was further purified by chiral HPLC on a CHIRACEL AD column with hexanes / EtOH (9/1) as eluent. The compound could be crystallized from hexanes / EtOAc or hexanes / EtOH (mp = 216.5-217.5 ° C). ¹ H-NMR (CDCl ₃ ): δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J = 8, 2 Hz), 4.89, 4.48 (1H, s), 4.47 (1H, m), 3.71, 3.48 (1H, m), 3.35 (1H, m), 3, 28-3.17 (1H, m), 2.95 (1H, m), 2.95, 2.81 (1H, m), 2.68 (2H, m), 2.45 (2H, m) , 2.37 (2H, m), 2.15 (1H, m), 1.93 (2H, m), 1.60 (1H, m), 1.38 (1H, m), 1.36 ( 3H, t, J = 6.0 Hz). MS: (MH) ⁺ 556.0.

EXAMPLE 8

(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)-N-methyloctahydro-2H-isoindol-2-carboxamid

(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) -N-methyloctahydro-2H-isoindol-2 -carboxamide

To a solution of ~ 20 mg (0.042 mmol) (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl ) octahydro-1H-isoindole (Example 6) in ~ 2 mL of dry methylene chloride at RT was added several drops of methyl isocyanate. The resulting mixture was stirred for 2 hours at RT. Several drops of 2N aq. NaOH was added to the reaction mixture. The organic layer was separated, dried over desiccant, filtered and the solvent removed under vacuum. The residue was purified by TLC eluting with EtOAc and the main product band isolated. The residue was taken up in EtOAc and the solids were filtered off. The solvent of the filtrate was removed in vacuo to give the title compound. ¹ H-NMR _(CDCl3): δ: 7.71 (1H, s), 7.23 (2H, s), 6.98 (2H, m), 6.85 (2H, m), 4.45 (1H, m), 4.00 (1H, m), 3.68 (1H, m), 3.36 (1H, m), 3.08 (1H, m), 2.93 (1H, m) , 2.77 (3H, s), 2.55 (1H, m), 2.45 (1H, m), 2.10 (1H, d, J = 12.5 Hz), 2.00-1, 70 (2H, m), 1.70-1.50 (1H, m), 1.30 (1H, m), 1.30 (3H, d, J = 6.0 Hz). MS: (MH ⁺ ) 533.5.

EXAMPLE 9

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-2H-isoindol-2-yl]-5-hydroxycyclopent-2-en-1-on

3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 yl] -5-hydroxycyclopent-2-en-1-one

To a solution of 20 mg (0.07 mmol) of 3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2-yl] cyclopent-2-en-1-one (Example 7) and 170 mg (0.39 mmol) of MoOPH in ~ 2 mL of dry THF under a nitrogen atmosphere at -78 ° C was added x0.076 ml (0.15 mmol) of a 2.0 M solution of KHMDS. The resulting mixture was stirred at -78 ° C for 2 hours then quenched by the addition of sat. aq. Quenched NH ₄ Cl. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over desiccant and filtered. The residue was purified by prep. TLC with CHCl ₃ / 2N NH ₃ in MeOH (9/1) as eluent to give the title compound as a mixture of diastereomers. ¹ H-NMR (CDCl ₃ ): δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J = 8, 2 Hz), 4.85, 4.71 (1H, s), 4.47 (1H, m), 4.20 (1H, m), 3.80-3.65 (1H, m), 3, 37 (1H, m), 3.25-3.08 (1H, m), 3.10-2.80 (3H, m), 2.58 (1H, m), 2.50-2.30 ( 1H, m), 2.15 (1H, m), 1.95 (2H, m), 1.35 (3H, d, J = 6.0 Hz). MS: (MH) ⁺ 572.5. The diastereomers were separated by HPLC on a CHIRACEL AS column with hexanes / EtOH (85/15) as eluent to give the individual diastereomers.

EXAMPLE 10

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(4-fluorphenyl)octahydro-2H-isoindol-2-yl]-4-hydroxycyclopent-2-en-1-on

3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H-isoindol-2 yl] -4-hydroxycyclopent-2-en-1-one

Step A: 4 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H- isoindol-2-yl] cyclopent-4-ene-1,3-dione

The title compound was prepared from (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy) -4- (4-fluorophenyl) octahydro-1H-isoindole ( Example 6) and cyclopentane-1,2,4-trione were prepared according to the method of Example 7. MS: (MH) ⁺ 570.0.

Step B: 3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2H- isoindol-2-yl] -4-hydroxycyclopent-2-en-1-one

The title compound was prepared from a mixture of diastereomers from the intermediate of Step A according to the procedure of Example 6, Step C, (NaBH ₄ in methanol). ¹ H-NMR _(CDCl3): rotamers; δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J = 8.2 Hz), 4.88-4 , 65 (2H, m), 4.46 (1H, m), 4.07 (0.5H, m), 3.83 (0.5H, m), 3.55 (1H, m), 3, 35 (1H, m), 3.28 (1H, m), 2.97 (2H, m), 2.92 (1H, m), 2.58 (1H, m), 2.43 (1H, m ), 2.25 (1H, m), 2.13 (1H, m), 2.05-1.85 (2H, m), 1.70-1.55 (2H, m), 1.30 ( 3H, 2d, J = 6.0 Hz). MS: (MH) ⁺ 572.5. The diastereomers were separated by HPLC on a CHIRACEL OD column with hexanes / EtOH (85/15) as eluent to give the individual diastereomers.

EXAMPLE 11

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluormethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-on

3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-2H-isoindol-2 -yl] cyclopent-2-en-1-one

Step A: 2- (2-Methylphenyl) -N-methoxy-N-methylacetamide

The title compound was prepared from 2- (methylphenyl) acetic acid according to the procedure for Example 1, Step A. ¹ H-NMR _(CDCl3): δ: 7.23 (4H, m), 3.83 (2H, s), 3.65 (3H, s), 3.28 (3H, s), 2.36 (3H, s).

Step B: 1- (2-Methylphenyl) but-3-en-2-one

The title compound was prepared from the intermediate of Step A according to the procedure of Example 1, Step B. ¹ H-NMR _(CDCl3): δ: 7.24 to 7.11 (4H, m), 6.42 (1H, dd, J ₁ = 14.2 Hz, J ₂ = 11 Hz), 6.34 (1H, d, J = 14.2Hz), 5.81 (1H, d, J = 11Hz), 3.90 (2H, s), 2.26 (3H, s).

Step C: 1E- and 1Z-tert-butyl - {[1- (2-methylbenzylidene) -prop-2-en-1-ylloxy} -dimethylsilane

The title compound was prepared from the intermediate of Step B according to the procedure of Example 1, Step C. ¹ H-NMR _(CDCl3): δ: 7.22 to 7.07 (4H, m), 6.40 (1H, dd, J ₁ = 13.2 Hz, J ₂ = 8.5 Hz), 5 , 85 (1H, s), 5.54 (1H, d, J = 13.2Hz), 5.19 (1H, d, J = 8.5Hz), 2.28 (3H, s).

Step D: Diethyl 4 - {[tert-butyl (dimethyl) silyl] oxy} -3- (2-methylphenyl) cyclohex-4-ene-1,2-dicarboxylate

The Title compound was prepared from the intermediate of Step C according to the method of Example 6, Step A, prepared and without further purification used.

Step E: Racemic diethyl (1S, 2S, 3R) -3- (2-methylphenyl) -4-oxocyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S) -3- (2-methylphenyl) -4-oxocyclohexane-1,2-dicarboxylate

The title compounds were prepared from the intermediate of Step D according to the method of Example 6, Step B. ¹ H-NMR _(CDCl3): δ: 7.26 to 7.09 (4H, m), 4.23 to 4.12 (2H, m), 3.90-3.80 (3H, m), 3.32 (1H, td, J ₁ = 13.0 Hz, J ₂ = 4.0 Hz), 3.28 (1H, t, J = 13 Hz), 2.67 (2H, m), 2, 50 (1H, m), 2.24 (3H, s), 2.09 (1H, m), 1.25 (3H, t, J = 7.2Hz), 0.83 (3H, t, J = 7.2 Hz).

Step F: Racemic diethyl (1S, 2S, 3R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S, 4R) -3- (2 methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate

The title compounds were prepared from the intermediate of Step E according to the method of Example 6, Step C. ¹ H-NMR _(CDCl3): δ: 7.20-7.10 (4H, m), 4.15-4.07 (2H, m), 3.88 to 3.66 (3H, m), 3.09 (1H, t), 2.83 (2H, m), 2.30 (3H, s), 2.24-2.15 (2H, m), 1.68 (1H, m), 1 , 57 (1H, m), 1.25 (3H, t, J = 7.2 Hz), 0.83 (3H, t, J = 7.2 Hz).

Step G: Diethyl (1S, 2S, 3R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate

The racemic mixture of diethyl (1S, 2S, 3R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate and diethyl (1R, 2R, 3S, 4R) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate (step F) was prepared by preparative Chiral HPLC using a CHIRACEL AD column separated with heptanes / i-PrOH (9/1) as eluant to give the desired first eluting isomer diethyl (1S, 2S, 4R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate according to the method of Example 6, step D.

Step H: Diethyl (1S, 2S, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (2-methylphenyl) cyclohexane-1,2 dicarboxylate

The title compound was prepared from the first eluting isomer diethyl (1S, 2S, 3R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexane-1,2-dicarboxylate (step G) and (1S) -1- [3 , 5-Bis (trifluoromethyl) phenyl] ethyl 2,2,2-trichloroethane imidoate (Example 6, Step E) according to the method of Example 6, Step F. ¹ H-NMR (CDCl ₃ ): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08-6.92 (4H, m), 4.25 (1H, q, J = 6.0 Hz), 4.20-4.10 (2H, m), 3.85-3.66 (2H, m), 3.42 (1H, m), 3.21 (1H, t ), 2.90-2.79 (2H, m), 2.35 (1H, m), 2.25 (1H, m), 2.22 (3H, s), 1.69-1.56 ( 2H, m), 1.30 (3H, d, J = 6.0 Hz), 1.23 (3H, t, J = 7.2 Hz), 0.77 (3H, t, J = 7.2 Hz). Unreacted starting alcohol could be recovered by purging the column with EtOAc and reused in the above reaction.

Step I: [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (2-methylphenyl) cyclohexane-1,2- diyl] dimethanol

The title compound was prepared from the intermediate of Step H according to the procedures of Example 6, Step G. ¹ H-NMR (CDCl ₃ ): δ: 7.64 (1H, s), 7.16 (2H, s), 7.04-6.91 (4H, m), 4.24 (1H, q, J = 6.0 Hz), 3.74 (1H, m), 3.60 (1H, m), 3.48 (1H, m), 3.35-3.20 (2H, m), 2, 90-2.70 (2H, m), 2.26 (1H, m), 2.21 (3H, s), 1.85 (1H, m), 1.62 (1H, m), 1.56 -1.42 (3H, m), 1.28 (3H, t, J = 6.0 Hz).

Step J: [(1S, 2R, 3R, 4S) -4 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (2-methylphenyl) cyclohexane-1,2- diel] di (methylene) dimethanesulphonate

The Title compound was prepared from the intermediate of Step I according to the method of Example 6, Step H, prepared and without further purification used.

Step K: (3aR, 4R, 5S, 7aS) -2-Benzyl-5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-1H -isoindole

The title compound was prepared from the intermediate of Step J and benzylamine according to the method of Example 6, Step I. ¹ H-NMR _(CDCl3): δ: 7.64 (1H, s) (, 7.32-7.25 (5H, m), 7.18 (2H, s), 7.04 to 6.97 4H, m), 4.25 (1H, q, J = 6.0 Hz), 3.75 (1H, d, J = 13.4 Hz), 3.65 (1H, d, J = 13.4 Hz), 3.40 (1H, m), 2.90 (2H, m), 2.54-2.30 (4H, m), 2.22 (3H, s), 2.02-1.85 (3H, m), 1.61 (1H, m), 1.33 (3H, t, J = 6.0 Hz), 1.30 (1H, m).

Step L: (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-1H-isoindole

The title compound was prepared from the intermediate of Step K according to the method of Example 6, Step J. ¹ H-NMR _(CDCl3): δ: 7.64 (1H, s), 7.18 (2H, s), 7.04 to 6.97 (4H, m), 4.25 (1H, q, J = 6.5 Hz), 3.40 (1H, m), 3.25 (1H, m), 2.90-2.75 (2H, m), 2.63 (1H, t), 2, 44 (1H, t), 2.35 (1H, m), 2.22 (3H, s), 2.05 (1H, m), 1.86-1.72 (2H, m), 1.61 (1H, m), 1.33-1.20 (5H, m).

Step M: 3 - [(3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-1H- isoindol-2-yl] cyclopent-2-en-1-one

The title compound was prepared from (3aR, 4R, 5S, 7aS) -5 - {(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-1H-isoindole (Step L) and cyclopentane-1,3-dione were prepared according to the method of Example 7. ¹ H-NMR _(CDCl3): rotamers δ: 7.64 (1H, s), 7.18 (2H, s), 7.04 to 6.97 (4H, m), 4.74, 4.53 (1H, s), 4.42 (1H, m), 3.68, 3.43 (1H, m), 3.50 (1H, m), 3.06 (1H, m), 2.93 ( 2H, m), 2.86, 2.76 (1H, m), 2.57 (1H, m), 2.40 (2H, m), 2.28 (3H, s), 2.20 (1H , m), 2.17 (1H, m), 2.10-1.94 (3H, m), 1.58 (1H, m), 1.40 (1H, m), 1.28 (3H, d, J = 6.0 Hz). MS: (MH) ⁺ 552.43.

By Application of procedures that are essentially comparable to those described above became the compounds of the following examples.

By Application of procedures that are essentially comparable to those described above became the compounds of the following examples.

Claims (13)

A compound of the formula I:

in the: R ^{1 is} selected from the group consisting of: 1) hydrogen, 2) C _1-6 alkyl which is unsubstituted or substituted by halogen, hydroxyl or phenyl, 3) cyclopentenone which is unsubstituted or substituted by hydroxyl or methyl 4) - (CO) -C _1-6 -alkyl, 5) - (CO) -NH ₂ , 6) - (CO) -NHC _1-6- alkyl, and 7) - (CO) -N ( C _1-6 alkyl) (C _1-6 alkyl); X is independently selected from the group consisting of: 1) hydrogen, 2) fluoro, and 3) methyl; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. The compound of claim 1 of the formula Ia:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. The compound according to claim 1 of the formula Ib:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. The compound of claim 1 wherein R ^{1 is} selected from the group consisting of: 1) hydrogen, 2) methyl, 3) 2-phenylethyl, 4) 2-hydroxyethyl, 5) cyclopent-2-en-1-one , 6) 5-hydroxycyclopent-2-en-1-one, 7) 4-hydroxycyclopent-2-en-1-one, 8) 2-methylcyclopent-2-en-1-one, 9) acetyl, 10) - (CO) -NH ₂ , 11) - (CO) -NHCH ₃ , and 12) - (CO) -N (CH ₃ ) CH ₃ . The compound of claim 1, wherein X is hydrogen is. The compound of claim 1, wherein X is fluorine. A compound according to claim 1 which is selected from the group consisting of:

and pharmaceutically acceptable salts thereof. The compound of claim 7, which is:

or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a inert carrier and a compound according to any one the previous claims or a pharmaceutically acceptable salt thereof. The use of a compound according to any the claims 1-8 for the production a drug for antagonizing the effect of the substance P at its receptor site or to block the neurokinin-1 receptor in a mammal. The use of a compound according to any the claims 1-8 for the production a drug for the treatment of a physiological disorder, the with a surplus on tachykinins in a mammal is related. The use according to claim 11, wherein said physiological disorder a disorder the bladder function is. The use according to claim 12, wherein the disorder is the Bladder function a cystitis, a bladder detrusor hyperreflexia, frequent Urinating and urinary incontinence is, including prevention or Treatment of hyperactive bladder with symptoms of urge incontinence, Urgency and frequency.